Substituted thiobarbitijric acids



Patented Jan. 12, 1954 SUBSTITUTED THIOBARBITURIC Aqlps.

A SALTS 'rm nsorj Wilbur J Doran,

Indianapolis, Ind., assignortto,

Eli "Lilly and Company, Indianapolis, 1nd,, a,

corporation of Indiana No Drawing. Application April 4, 125,2;Serial-No. 280,653?" 6 Claima, (Cl. 260-260) This-inven n reltes..torbar t r c, a ds mere. ar cu ar y to e t in; 5-d su t t te methvrz-thiob tn cid d a s. he of. e ithetre arat on,

Thecompounds of, the present invention may bere re entcdby th fo mulwherein-R represents amember of thegroupconsisting ofthe ethyl'and-allyl radicals, and R1 isa member of the group'consisting of thl-methyle butyl and l-ethylpropyllradicals, and X represents hydrogenwhen the compound is an acid, and represents a metallicor metallic-likeradical when the compoundis a salt.

The 5-,5-disubstituted. V 1'-methyl-Z-thiobarbituric acids of thisinvention' are White, crystalline solids which are insoluble inwateriand soluble in the common organic solvents. The salts ofthe newsubstituted 1-methyl-2ethiobarbituric acids are solids which aregenerally soluble in water and alcohol, and insoluble in most organicsolvents. The new compounds have utility as hypnotics and anesthetics,and are particularly valuable in that they are characterized by anunusually short hypnotic action. Compounds with extremely short actionsuch as is displayed by thecompounds of this invention have long beensought, since theywould be especially useful in connection 'withminorsurgical measures. The substituted 1 methyl 2 thiobarbituric acids canbe prepared by alternative procedures. Thus, for example, a diester ofan appropriately substituted malonic acid can be condensed withNr-methylthiourea in. the presence of an alkaline catalyst such assodium ethoxide or thelike, to form the desired suizastituted l-methyl-2-thiobarbituric acid. Alternatively, an appropriately substitutedcyanoacetic ester can be condensed with N-methylthiourea to form thecorrespondingly substituted, imino-2-thiobarbituric acid, which is thenhydrolyzed with a mineral acid to remoy the imino group and produce thedesired 1-methyl 2-thiobarbituric acid. 7

Saltsofthe thiobarbituric acids of thisinvention are readily prepared bythe usual methods of the art, as, for example, by interreaction ofstoichiometrically equivalent quantities of the selected acid and a.base, containing. the desired metallic,or..metallic:1ike. (i. e.,substituted ammonium) cation, ina ,mutual solvent, followed by remoyalofthe solvent to leave the salt as a resid l, The preferred salts. are thepharmaceutically useful "salts, i.- e. salts which are not substantiallymore toxic than the acids from which they, are derived, and whichcan bincorporated in. pharmaceutical extending media, liquid'or solid, forthe. preparation. of; therapeuticallyrusee, ful. compositions.Illustrative. examples. unsuitable saltsincludethoseof thealkaltmetalser g sodium and potassium, alkaline, earth metals, e. a.calcium, and substituted ammonium radicals, e. g. ethanolamine,ethylenediamine, tetraalkyl ammonium hydroxide, and, the like.

The following examples, mor specifically illustrate the preparation ofthe substituted 1- methyI-Z-thiobarbituric acids of the invention, andtheir salts.

X MILE 1 Preparation of 1-mcthyZ-5 -ethyl-5-(fl-mcthz L- butyl)-2-thz'obarbituric acid To a solution of 38 g (1.65. mols), of-sodiumin760 cc. of absolute alcoholare addedfiilqg. (1.65 mols) of the ethyl,ester, of, ethyl fl-methyli butyll-cyanoacetic and [prepared asdescribed by Tabern et al., J; AI C. S.; 56, 1939 (1934)], and 135 g.(1.5 mols) or methylthiQlrea. The mixture is refluxed, for about ,24,hours, and the resulting reaction mixture, containing l-methyl- 5 ethyl5 (1f methylbutyl) 1 imino-zb tu ic c d ormed he eact n... cool d, a urd- Q 1 ab i t .091s f. ql dl arr n diox e ntained a a ee eaten. A ter eca on io i e ha ubsta ti lly. m l t ly reacted, 2liters ofWaterareadded-to themix;- re and e i hat e arates s; xtra t da ith 3 s csi 00, Qc-11 mns i the Thecpmr ed he x ac are .e. s fied-; i 11 twp 750cc. portions of 5 percent aqueoussodium by: droxide, and the combinedalkaline extractscontaining the sodium salt: of. the, imino-2-thiobarbituric acid. areacidifiedwith dilute acetic acid whereupon l -methyl 5-eth yl;5-,( 1 f -methylbutyl) qr h obarbiw e c d. e ip e es as an oilwhich solidifies onstanding The solid-sub stance s e -.011r aehet i itWater ntler crystallized from aqueous ethanoh a 0.1 p ethyle ihy -5methylbutyl)-4-imino-2-thiobarbituric acid prepared according to theforegoing procedure and melting t b ut 98,? Q. a e nixe th a solutionof;1Q cc.- ,(0.l2 mol qfconcentrated hydrochloric acidin 250 cc. ofwater. The mixture is refluxed with stirring; for about one hourWhBI'BHpOIlaIJ, oil comprising l-methyl-5-ethyl-r5- (1-me thylbutyl)-2-thiobarbituric-acid separates. The oily layer solidifies on coolingandis filtered off, washed with water andrecrystallizedfrom aqueousethanol;

1 methyl 7 5 ethyl 5 1- methylbutyl) 6 2-thiobarbituric acid thusprepared melted 6 at about 55-58 C. i

Analysis.--Calculated fol-CnHzoNzOzS; N, 10.93; Found: N, 10.70.

Preparation of the sodium salt of 1-methyl-5- ethyl-5- (1 -methylbatyl)-,2-thiobarbz'taric acid 25 g. of 1-methyl-5-ethyl-5-(1f -methylbutyl)-2-thiobarbituric acid are dissolved in 100 cc. of absolute ethanol andto the resulting solution is added gradually and with stirring anethanol solution of sodium ethylate until the pH of the EXAMPLE 3Preparation of 1-methyZ-5-ethyZ-5-(1-eth1 Z- prom/Z) -2-thiobarbituricacid The procedure of Example 1 is followed, except that the ethyl esterof ethyl-(l-ethylpropyD-cyanoacetic acid [prepared by the method ofTabern et al., J. A. C. 55.: 56, 1939 (1934)] is used. The intermediatel-methyl-Eiethyl-5-(1 ethylpropyl-4 imino-Z thiobarbituric acid which isformed, is hydrolyzed to yield 1-methyl-5-ethyl 5-(1' ethylpropyl) 2-thiobarbituric acid, which when recrystallized from aqueous ethanolmelts at about 57-61 C.

EXAMPLE; 4

1 Preparation of 1-methyZ-5-alZyl-5-(1-methylbatyl) -2-thiobarbitaricacid The procedure of Example 1 is followed, except that ethylallyl-(l-methylbutyl)-cyano acetate, prepared by the method described inBritish Patent 613,704, granted December 2, 1948, is used. Theintermediate 1-methyl-5-allyl-5- (1'-methy1butyl)-4-imino -2-thiobarbituric acid which is formed, is hydrolyzed to yield l-methyl-5-a1lyl-5- (1'-methylbutyl) -2-thiobarbituric acid, which whenrecrystallized from aqueous ethanol melts at about 69-7 C.

A solution of 8.4 g. (0.1 mol) potassium ethylate in-20 cc. of absoluteethanol is added to a solution of 22.6 g. (0.1 mol) of 1-methyl-5-allyl--(1'-methylbutyl)-2-thiobarbituric acid in 50 cc. of anhydrous ethanol.The resulting mixture is filtered, and the filtrate is evaporated todryness in vacuo. A white solid, consisting of the potassium salt of1-methyl-5-allyl-5-(l-methylbutyl)-2-thiobarbituric acid, is recovered.

EXAMPLE 5 Preparation of 1-methyZ-5-aZZyZ-5-(1'-ethylpropyl)-2-thz'obarbituric acid The procedure of Example 1 is followed, exceptthat ethyl allyl-(l-ethylpropyl)-cyanoacetate, prepared according to thedisclosure of British Patent 613,705, granted December 2, 1948, is used.The 1 methyl 5 allyl-5-(1-ethylpropyl)-4-imino-2-thiobarbituric acidwhich is formed as an intermediate in the process is hydrolyzed to yield1-methyl-5-allyl-5-(1'ethylpropyD-Z-thiobarbituric acid, which melts atabout 53-57 C. after recrystallization from dilute ethanol.

EXAMPLE 6 The compounds of the present invention can also be prepared bythe process wherein a suitably substituted malonic ester is condensedwith methylthiourea. The following description, in which the preparationof 1-methyl-5-ethyl-5- (1'-methylbutyl)-2-thiobarbituric acid isspecifically illustrated, exemplifies the preparation of the newsubstituted thiobarbituric acids.

11.5 g. (0.5 mol) of sodium are dissolved in 200 cc. of absolutealcohol. To the solution are added 36 g. (0.4 mol) of methylthiourea and112 g. (0.4 mol) of ethyl (l-methylbutyl) ethyl malonate'and the mixtureis refluxed for 20 hours. The reaction mixture is cooled and poured overan excess of Dry Ice. The mixture is allowed to stand until about pH 7in reaction, as shown by indicator paper.; 700 cc. ofwater are thenadded and the resulting oily mixture is extracted with three successive250 cc. portions of ether. The combined ether extracts are'extractedtwice with 250 cc. portions of 5 percent sodium hydroxide solution. Thecombined alkaline extracts are cooled and neutralized with dilute aceticacid, and the l-methyl-5-ethyl-5- (l -methylbutyl) -2-thiobarbituricacid formed in the reaction separates as an oil. The oily mixture isextracted with 3 successive 200 cc. portions of ether, the combinedether extracts are dried and the ether distilled off. The residue isfractionally distilled under reduced pressure and the portion boiling atabout -152 at 2 mm. pressure is collected.

The 1-methy1-5-ethyl-5-(1'-methylbutyl) 2- thiobarbituric acid thusprepared was found to melt at about 54-57 C. after recrystallizationfrom aqueous ethanol.

I claim:

1. A compound chosen from the group consisting of thiobarbituric acidsrepresented by the formula wherein R is a member of the group consistingof ethyl and allyl radicals and R1 is a member of the group consistingof l-ethylpropyl and 1- methylbutyl radicals; and their pharmaceutical-1y useful salts.

2. l-methyl 5 ethyl 5 -(1'-methylbutyl) -2 thiobarbituric acid.

3. l-methyl-5-ethyl 5-(1' ethylpropyl) 2- thiobarbituric acid.

4. l-methyl-S-allyl 5-(1 methylbutyl) 2- thiobarbituric acid.

5. l-methyl 5 allyl 5 (1'-ethylpropyl)-2- thiobarbituric acid.

6. Sodium 1-methyl-5 ethyl-5 (1' methylbutyl) -2-thiobarbituric acid.

WILBUR J. DORAN.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,152,512 Volweiler et a1 Mar. 28, 1939 2,187,728 ChristiansenJan. 23, 1940 OTHER REFERENCES Crossley et al.: J. Org. Chem. 5, 238-243(1940). Volweiler et al.: J. Am. Chem. Soc., 57, 1961-3

1. A COMPOUND CHOSEN FROM THE GROUP CONSISTING OF THIOBARBITURIC ACIDSREPRESENTED BY THE FORMULA